Two Case Studies of the Transfer of Near-Infrared Methods for the Analysis of Pharmaceutical Solid Dosage Forms

Significance of the Topic

Near-infrared (NIR) spectroscopy is increasingly adopted in pharmaceutical quality control for non-destructive assay of tablets and capsules. Reliable transfer of multivariate calibration models between instruments is a prerequisite for routine deployment across production and QC sites because it avoids laborious recalibration and revalidation. This study evaluates the practical feasibility of direct method transfer between matched Fourier transform NIR (FT-NIR) systems using two contrasting tablet types to probe effects of sample physical properties and sampling mode on transfer performance.

Objectives and Study Overview

• Assess whether calibration models developed on a primary FT-NIR instrument can be applied unchanged on a target instrument.
• Compare transmission and reflectance sampling for two tablet types that differ in size, shape, and active ingredient loading.
• Quantify transfer performance using standard chemometric metrics (R2, RMSEC, RMSEP) and inspect bias and residual behaviour.

Methodology

• Samples: Two sets of marketed/clinical tablets were used: small, thin, round tablets with <10% active ingredient (measured in transmission) and larger, thicker oval tablets with >40% active ingredient (measured in reflectance).
• Instrument: Thermo Scientific Antaris FT-NIR Method Development Sampling System (see Instrumentation Used section for details).
• Spectral acquisition: Reflectance — 50 scans/tablet, 8 cm-1 resolution, spectral range 4000–10000 cm-1; Transmission — 100 scans/tablet, 8 cm-1 resolution, spectral range 6000–12000 cm-1. Reflectance measurements were taken on the unscored tablet side.
• Chemometrics: Partial Least Squares (PLS) regression models were built for each tablet set. Pretreatment included a second derivative and Norris smoothing segments. Model specifics: small tablets (transmission) — PLS with 4 factors, second derivative, Norris 25-point segment, spectral interval ~8924–11209 cm-1; large tablets (reflectance) — PLS with 3 factors, second derivative, Norris 11-point segment, spectral interval ~4181–9169 cm-1.
• Transfer test: Models developed on the primary instrument were applied without modification to a matched target Antaris FT-NIR instrument; prediction errors and bias were evaluated.

Instrumentation Used

• Thermo Scientific Antaris FT-NIR Method Development Sampling System.
• Sampling modules: tablet detector and integrating sphere modules enabling non-destructive transmission and diffuse reflectance measurements without relocating samples.
• Acquisition parameters as listed above (scans, resolution, spectral ranges for each mode).

Main Results and Discussion

• Small tablets (transmission): The transmission PLS model performed excellently on the primary instrument (R2 ≈ 0.9996, RMSEC = 0.247 mg/tablet), distinguishing clinical content levels. When applied to the target instrument the RMSEP increased to 0.486 mg/tablet but no systematic bias was detected, indicating acceptable transfer fidelity for quantitative screening.
• Large tablets (reflectance): The reflectance PLS model yielded R2 ≈ 0.9864 and RMSEC = 1.65% on the primary instrument. Model transfer to the target instrument produced RMSEP ≈ 1.64%, effectively matching calibration performance and demonstrating seamless transfer. A separate observation showed a 3.5% bias between measurements taken on the scored versus unscored tablet side, highlighting a sample-handling caveat for reflectance assays.
• Comparative assessment: Transmission sampling is preferable for small, highly transmissive tablets with low active load; reflectance is superior for larger, less transmissive tablets with higher active content. Across both cases, matched FT-NIR instruments with internal laser frequency referencing and comparable components delivered highly similar results, minimizing the need for instrument-matching algorithms or difference-correction methods.
• Tabulated comparison of identical tablets measured on primary vs target instruments showed percentage differences typically within ±2%, supporting the conclusion of instrument sameness under the tested conditions.

Benefits and Practical Applications

• Direct method transfer reduces time and resources otherwise spent on re-developing or re-validating calibrations at multiple sites.
• Non-destructive, rapid assay enables in-line or at-line QC for tablet content uniformity and batch release screening.
• Model robustness across matched FT-NIR systems supports centralized calibration development and decentralized deployment in manufacturing networks.
• Knowledge of sampling-mode dependencies (transmission vs reflectance) aids method selection based on tablet geometry and formulation.

Future Trends and Applications

• Wider adoption of standardized, factory-matched FT-NIR platforms could further lower barriers to direct method transfer in regulated environments.
• Development of automated diagnostic tools to flag sampling-related biases (e.g., scored vs unscored surfaces) will improve routine reflectance assays.
• Hybrid strategies combining instrument design standardization with lightweight transfer algorithms may extend transferability across a broader range of hardware generations and manufacturers.
• Integration with process analytical technology (PAT) frameworks and digital records could streamline regulatory acceptance of transferred models through robust traceability and audit trails.

Conclusion

The study demonstrates that, when instruments share a matched FT-NIR design and stable internal referencing (laser-based wavelength calibration), chemometric models for tablet assay can be transferred between systems with minimal degradation in performance. Transmission sampling best suits small, low-load tablets while reflectance sampling is preferable for larger, high-load tablets; attention to sample orientation and surface (scored vs unscored) is important for reflectance workflows. Overall, instrument sameness combined with appropriate preprocessing and PLS modeling enabled seamless transfer in the examined cases, promising operational efficiencies for pharmaceutical QC.

References

1. Thermo Fisher Scientific. Application Note 50646: Two Case Studies of the Transfer of Near-Infrared Methods for the Analysis of Pharmaceutical Solid Dosage Forms. 2008.